The present invention relates to a new method of treating prolonged critical illness, non-coping stress, both physically and mentally, frail-elderly syndrome and other conditions involving a similar neuroendocrine pattern.
Critically ill patients, supported with intensive care for weeks or months indifferently present a feeding-resistant xe2x80x9cwasting syndromexe2x80x9d, characterized by ongoing loss of protein whereas fat stores are paradoxically preserved or even built up. Consequences of this wasting are increased urea production related to muscle weakness, osteoporosis, deficient healing of wounds and fractures and impaired recovery of failing organ systems, together further prolonging the dependency on expensive intensive care support.
The present inventor were the first to establish that, from a neuroendocrine perspective, the chronic phase of intensive care-supported severe illness is different from the acute post-resuscitation phase. Immediately after onset of acute illness or trauma, anterior pituitary function is activated, which is thought to contribute to the metabolic adaptation essential for survival. It has always been assumed that the neuroendocrine pattern found during the acute phase is similar to the one found during the chronic stages of critical illness. In contrast however, the chronic phase of protracted critical illness is characterized by a uniformly suppressed pulsatile secretion of growth hormone (GH), thyrotropin (TSH) and prolactin (PRL), related to low serum levels of ICF I IGFBP-3, acid-labile subunit (ALS), thyroid hormones and leptin.
The present inventor found that the relative impairment of pulsatile GH and TSH release is due to a reduced content or activity of hypothalamic TRH and of the putative endogenous ligand for the GH-secretagogue receptor.
It was therefore hypothesized by the present inventor that the impaired hypothalamic and anterior pituitary hormone secretion, as it occurs distinctively in the chronic phase of critical illness, contributes to the development and maintenance of the wasting syndrome. The inventor assumed that the wasting syndrome is caused by an increase in catabolism due to impaired pulsatile TSH secretion and a shortage of thyroid hormones and a simultaneous disruption of the anabolism due to a decrease in pulsatile growth hormone secretion and GH-dependent IGF""s and IGFBP""s.
It was found that pulsatile secretion of GH and TSH during protracted critical illness-can be reactivated by the continuous and combined infusion of the GH-secretagogue GHRP-2 and TRH for 21-45 h, which elicits a proportionate rise in circulating IGF-I, IGFBP-3, ALS, leptin and thyroid hormones without altering serum cortisol levels.
In the research that led to the present invention this mechanism was further explored by extending the infusion time of GHRP-2+TRH to 5 days which allows a first limited evaluation of metabolic effectiveness of this novel endocrine strategy.
This led the present inventor to conclude that infusion of GHRP-2+TRH for 5 days in protracted critical illness reactivated the blunted GH and TSH secretion, with preserved peripheral responsiveness and feedback inhibition and without affecting serum cortisol. Concomitantly, a reversible shift towards anabolic metabolism (reduced catabolism and increased anabolism) was induced, as indicated by biochemical markers. Hereby, the first evidence of effectiveness of GHRP-2+TRH for treatment of the xe2x80x9cwasting syndromexe2x80x9d in protracted critical illness was provided.
In more general terms it was concluded that simultaneous administration of a GHRP together with TRH is capable of correcting the secretion of growth hormone and TSH after which the endogenous feed-back systems are again capable of normalizing both the level of growth hormone and TSH secreted and the peripheral effects that occur as a reaction on the activity of growth hormone and TSH. Thus, the anabolism is improved and the increased catabolism is reduced.
As an alternative, in conditions involving impairment of only one axis administration of only one of the two compounds can be used for treatment.
Based on these observations, the present invention provides a method of treating protracted critical illness by administering to a subject suffering from the illness an amount of Thyroid Releasing Hormone (TRH) and of Growth Hormone-Releasing Peptide (GHRP) suitable to reactivate the blunted anterior pituitary hormone release mechanism.
More in general, the invention relates to, methods of treating conditions which involve a blunted anterior pituitary hormone release pattern, comprising the administration to a subject, suffering from a condition involving the blunted anterior pituitary hormone pattern, of an amount of Thyroid Releasing Hormone (TRH) and of Growth Hormone-Releasing Peptide (GHRP) suitable to reactivate the blunted anterior pituitary hormone release mechanism. Such conditions are for example critical illness, non-coping mental and physical stress and the frail-elderly syndrome. These conditions are further defined in Brown., I. et al., International Journal of Rehabilitation Research 18, 93-102 (1995)
The invention further relates to a therapeutical composition containing GHRP and TRH in an amount and ratio sufficient to be suitable to reactivate the blunted anterior pituitary hormone release mechanism.
The present invention can be used for the treatment of the wasting syndrome that is found in patients suffering from protracted critical illness. However, the treatment of the invention can also be used for indications that involve a related blunting of the anterior pituitary release mechanism. This is based on the observation that various other conditions are thought to involve a neuroendocrine pattern that is similar to the one found in chronic illness. Such conditions are for example non-coping stress, both physical and mental, and the so-called frail-elderly syndrome, which is found in some but not all aging people and is for example characterized by a tendency to break bones such as hips etc. The invention thus also applies to methods of treating these types of conditions.
Optionally the administration of GHRP and TRH can be supplemented with Luteinizing Hormone Releasing Hormone (LHRH). A shortage of pulsatile LH secretion can lead to testosterone deficiency in males, which in turn can cause an increase in catabolism. It has been found that LHRH alone has no effect, but in combination with TRH and/or GHRP it is found to be effective in lowering catabolism, which is the result of a testosterone deficiency.
The term xe2x80x9cGHRPxe2x80x9d as used in this application is intended to encompass every protein or peptide or non-peptide analogue that is capable of binding to the Growth Hormone-Releasing Peptide-Receptor. Although an endogenous ligand for this receptor has not yet been identified, various artificial ligands have been designed that are capable of binding to the receptor. Examples of these are xe2x80x9cMK-0677xe2x80x9d and others.
This application refers to xe2x80x9csimultaneous application of GHRP and TRHxe2x80x9d. However, this phrase is not intended to limit the invention to cases in which GHRP and TRH are actually administered at the same time. Rather, the invention also relates to situations in which only one of two anterior pituitary axes is suppressed (e.g. TRH for only blunted TSH secretion and GHRP for only blunted GH secretion).
The present invention further relates to therapeutical compositions comprising GHRP and TRH in an amount and ratio sufficient to be suitable to reactivate the blunted anterior pituitary hormone release mechanism. Such amounts can for example vary between 0.01 and 10 xcexcg/kg/h for GHRP and 0.01 and 10 xcexcg/kg/h for TRH when given by infusion. Other administration forms can require other amounts. The ratio between the two varies for example between 0.5 and 4, more in particular between 0.5 and 2. In addition, in particular for the treatment of male patients such therapeutic composition can be supplemented with a suitable amount of LHRH to eliminate the effects of testosterone deficiency. LHRH can also be used with either TRH or GHRP alone.
In the Example that follows, metabolic effectiveness of the releasing peptides in the wasting condition associated with protracted critical illness was assessed by studying biochemical markers of catabolism such as urea production and urinary excretion of collagen crosslinks and markers of anabolism such as serum concentrations of osteocalcin and leptin.
Fourteen patients (68xc2x111y), critically ill for 40xc2x128 days, were studied for 10 days. Blood was sampled overnight every 20 minutes on night 0, 5 and 10 and daily at 06:00 h. 24 h urine was collected in HCl. After a first nocturnal profile, patients received 5 days placebo and 5 days GHRP-2+TRH (1+1 xcexcg/kg/h), in a random order. Serum concentrations of GH, IGF-I, IGFBP-1, IGFBP-3, ALS, IGFBP4, IGFBP-5, insulin, cortisol, TSH, T4, T3, rT3, prolactin (PRL), osteocalcin (OC), urea, creatinine as well as deoxypyridinoline/creatinine in 24 h urine (DPD) were determined. Pulsatile GH secretion was quantified by deconvolution analysis,
It was then found that at baseline, mean nocturnal GH concentrations (meanxc2x1SD 1.04xc2x10.69 xcexcg/L, median 0.75 xcexcg/L) and GH pulse amplitude (0.10xc2x10.11 xcexcg/Lv/min, median 0.05 xcexcg/Lv/min) were related to low serum IGF I (87xc2x18 xcexcg/L), IGFBP-3 (1.41xc2x10.21 mg/L) and ALS (6.45xc2x10.88 mg/L). Serum concentrations of IGFBP-1 (10.8xc2x16.5 xcexcg/L) related inversely to serum IGFBP-3; insulin (36xc2x136 xcexcIU/mL) related positively to ALS. Nocturnal TSH (1.30xc2x11.33 mIU/L, median 0.89 mIU/L) and PRL (10.0xc2x13.2 xcexcg/L) levels were low-normal, in the presence of low T3 (0.85xc2x10.24 nmol/L) and T4 (77xc2x125 nmol/L) and elevated cortisol (424xc2x149 nmol/L). Levels of OC (29.5xc2x114.3 ng/mL), a biochemical marker of bone formation, and of the stimulatory IGFBP-5 (379xc2x1124 xcexcg/L) were reduced in relation to the suppressed GH-IGF(BP)-axis, whereas markers of catabolism such as DPD (106xc2x180 nmol/-mmol) and urea/creatinine ratio (UCR: 84xc2x139) as well as the inhibitory IGFBP-4 (877xc2x1204 [xcexcg/L) were all elevated, related positively to IGFBP-1 and inversely to thyroid hormone concentrations. Serum leptin levels (15.8xc2x113.1 xcexcg/L, median 10.8 xcexcg/L) were related to the GH dependent IGF(BP)""s and to bone turnover (OC and DPD).
Placebo infusion during the first 5 days decreased or did not alter the studied parameters. After days GHRP-2+TRH infusion, pulsatile GH secretion, TSH and PRL levels were (still) elevated. Within 2 days, IGF-1, IGFBP-3, ALS, IGFBP-5, leptin, T4 and T3 had increased to (near) normal levels and UCR had decreased with a mean 17%, further remaining stable until day 5. Five days GHRP-2+TRH increased OC by 19xc2x17% vs. xe2x88x926xc2x15% with placebo (P=0.03) and reversed the spontaneous IGFBP-1 rise. Infusing placebo following GHRP2+TRH infusion returned all hormonal levels to pretreatment values, except IGFBP-3 and IGFBP-5, which remained slightly higher, and allowed UCR to rise again. Reverse T3, cortisal, IGFBP-4 and DPD were unaltered